PROJECT SUMMARY This K08 career development award will facilitate the development of the PI into a clinician-scientist with an independent research program focused on humoral and cellular immunity of MS and other neurological disorders. The PI and her coworkers have recently reported on the prevalence and mechanisms antibodies to axoglial antigens in neurological diseases, e.g. CIDP and autoimmune encephalitis (Patterson et al. 2018, Burnor et al., 2018). This work demonstrates functional and structural consequences of autoimmunity to the axoglial apparatus in the pathogenesis of neurological diseases. The scientific program in this grant expands on this prior work, focusing axoglial autoimmunity in MS, an exciting new avenue of research with the potential to explain the dual pathology of both myelin and underlying axons in MS, as well as the substantial heterogeneity in the clinical course and outcomes that exists across patients. The modulating more study are to: (1) test matched frequencies as MRI trajectories central hypothesis of this proposal is that autoimmunity to the axoglial apparatus plays a role in MS pathogenesis and that patients with autoimmunity to the axoglial apparatus will experience severe axonal loss and consequently higher r ate s of brain atrophy . whether MS patients are more likely to have axoglial autoantibodies compared to age- healthy controls and controls with other inflammatory neurological diseases, (2) enumerate the and proinf lammatory potential of axoglial- reactive T cells in MS patients versus controls, and (3) a proof of principle, axoglial autoimmunity will be measured in subsets of MS patients defined based on measures of differing rates of atrophy to test the hypothesis that axoglial autoimmunity correlates with of brain atrophy. The objectives of the proposed These studies will lead to not only a better understanding of the pathogenesis and heterogeneity that exists in the spectrum of MS but also develop specific for tools to better monitor relevant antigen- responses and potentially to better prognosticate and possibly revisit more individualized strategies antigen-specific therapies. The PI will be guided by three mentors with distinct areas of expertise that are necessary to complete this project. Dr. Bar-Or is a world regulation expert in molecular and cellular immunology studying the principles of immune and immune neural interactions in MS;Dr. Scherer is an expert on the molecular organization of myelinated axons; and Dr. Lancaster is a leading expert in the field CNS autoimmunity, and particularly of antibody-mediated neurological diseases with extensive experience in the discovery of novel autoantigens, including axoglial apparatus molecules. A training plan to assist the PI in developing new research skills is an integral part of this application. In addition to completing the proposed research, the applicant will engage in a rigorous program of didactic courses and mentoring by experts in cellular and molecular immunology, brain imaging, and biostatistics. She will gain expertise in identification of immunodominant epitopes using overlapping peptide libraries, immunospot assays, cell proliferation assays, multiparametric flow cytometry, and statistical methodologies relevant to translational research as well as gain a working knowledge of development of recombinant MHC receptors and advanced MRI analytic techniques (MIMoSA and SuBLIME). Since this project involves both human subjects, specific training in the ethical concerns involved is integrated into the training plan. The applicant's progress and attainment of specific benchmarks in research and career development will be regularly reviewed by her mentors who have extensive experience in training junior investigators and facilitating their transition to independent research careers. Completion of the proposed study will be facilitated by an institutional environment that prioritizes collaboration and provides exemplary research and career support. Through the proposed study, the applicant will make significant contributions to the understanding of axoglial autoimmunity in neurological diseases and novel tools necessary for future projects examining T-cell mediated axoglial immunity in not only MS but also other neurological diseases such as autoimmune encephalitis and CIDP.